Project Summary/Abstract: Primary brain tumors, gliomas, have thus far evaded effective treatment making them a tremendous challenge clinically. This is in part due to the unusual ability of gliomas to infiltrate surrounding brain making surgical resection difficult. Tumor cells can move through the brain parenchyma, following white matter tracts or along blood vessels. Ultimately many glioma cells associate with blood vessels, presumably to gain enhanced access to nutrients. In a recent study, we show that glioma cells are attracted to cerebral vessels by responding to bradykinin which is produced by vascular endothelial cells. Once associated with blood vessels, glioma cells co-opt the vasculature and eventually induce vessel sprouting and angiogenesis. Understanding how gliomas alter the physiology of the existing cerebral vasculature is the primary objective of this grant. We hypothesize that the vascular association provides an intrinsic advantage and that gliomas actively regulate the behavior of the associated blood vessel. More specifically we hypothesize that (1) vessel associated glioma cells displace astrocytic endfeet from the blood vessels; (2) this disrupts normal astrocyte-vascular coupling as astrocyte-derived vasoactive molecules fail to reach vascular smooth muscle cells; (3) displacement of astrocytic endfeet leads to a breakdown of the blood-brain barrier; and (4) once attached to vessels, glioma cells actively regulate vascular tone through the release of vasoactive compounds. These hypotheses will be tested using a clinically relevant animal model of glioma employing a combination of single- and multi-photon imaging studies in situ and in vivo. These studies have the potential to elucidate novel ways to interfere with the destructive biology of these deadly tumors in the future.